Department of Internal Medicine, Institute of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul 06273, Republic of Korea.
Department of Surgery, Thyroid Cancer Center, Institute of Refractory Thyroid Cancer, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
Int J Mol Sci. 2023 Nov 16;24(22):16413. doi: 10.3390/ijms242216413.
Thyroid cancer is the most well-known type of endocrine cancer that is easily treatable and can be completely cured in most cases. Nonetheless, anti-cancer drug-resistant metastasis or recurrence may occur and lead to the failure of cancer therapy, which eventually leads to the death of a patient with cancer. This study aimed to detect novel thyroid cancer target candidates based on validating and identifying one of many anti-cancer drug-resistant targets in patient-derived sorafenib-resistant papillary thyroid cancer (PTC). We focused on targeting the sarco/endoplasmic reticulum calcium ATPase (SERCA) in patient-derived sorafenib-resistant PTC cells compared with patient-derived sorafenib-sensitive PTC cells. We discovered novel SERCA inhibitors (candidates 33 and 36) by virtual screening. These candidates are novel SERCA inhibitors that lead to remarkable tumor shrinkage in a xenograft tumor model of sorafenib-resistant patient-derived PTC cells. These results are clinically valuable for the progression of novel combinatorial strategies that facultatively and efficiently target extremely malignant cancer cells, such as anti-cancer drug-resistant PTC cells.
甲状腺癌是最著名的内分泌癌之一，在大多数情况下，这种癌症易于治疗并且可以完全治愈。然而，抗癌症药物耐药性转移或复发可能会发生，并导致癌症治疗失败，最终导致癌症患者死亡。本研究旨在基于验证和鉴定患者来源的索拉非尼耐药甲状腺乳头状癌（PTC）中许多抗癌症药物耐药靶标之一，来检测新的甲状腺癌靶标候选物。我们专注于靶向患者来源的索拉非尼耐药 PTC 细胞中的肌浆/内质网钙 ATP 酶（SERCA），与患者来源的索拉非尼敏感 PTC 细胞相比。我们通过虚拟筛选发现了新型 SERCA 抑制剂（候选物 33 和 36）。这些候选物是新型 SERCA 抑制剂，可导致索拉非尼耐药患者来源 PTC 细胞的异种移植肿瘤模型中的肿瘤明显缩小。这些结果对于开发新型组合策略具有重要的临床价值，这些策略可以选择性和有效地靶向极其恶性的癌细胞，如抗癌症药物耐药性 PTC 细胞。
